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C Pedone

Publications and source records attributed to C Pedone.

At least 19 recordsLinked to original sources
PubMed2006

Synthesis, characterization and hybridization studies of new nucleo-gamma-peptides based on diaminobutyric acid.

In the present work, we report the synthesis and the characterization of a new chiral nucleoaminoacid, in which a diaminobutyric moiety is connected to the DNA nucleobase by an amidic bond, and its oligomerization to give the corresponding nucleo-gamma-peptide. The ability of this synthetic polymer to bind complementary DNA was studied in order to explore its possible use in antigene/antisense or diagnostic applications. Our interest in the presented DNA analogue was also supported by the importance of gamma-aminoacid-containing compounds in natural products of biological activity and by the known stability of gamma-peptides to enzymatic degradation. Furthermore, our work could contribute to the study of the role of nucleopeptides as prebiotic material in a PNA world that could successively lead to the actual DNA/RNA/protein world, as recently assumed.

Aminobutyrates↗
PubMed2005

Conformational analysis by NMR and distance geometry techniques of a peptide mimetic of the third helix of the Antennapedia homeodomain.

The Antennapedia homeodomain structure consists of four helices. The helices II and III are connected by a tripeptide that forms a turn, and constitute the well-known helix-turn-helix motif. The recognition helix penetrates the DNA major groove, gives specific protein-DNA contacts and forms direct, or water-mediated, intermolecular hydrogen bonds. It was suggested that helix III (and perhaps also helix IV) might represent the recognition helix of Antennapedia homeodomain, which makes contact with the surface of the major groove of the DNA. In an attempt to clarify the helix III capabilities of assuming an helical conformation when separated from the rest of the protein, we carried out the structural determination of the recognition helix III in different solvent media. The conformational study of fragments 42-53, where residues W48 and F49, not involved in the protein-DNA interaction, were substituted by two alanines, was conducted in sodium dodecyl sulfate (SDS), trifluoroethanol (TFE) and TFE/water, using circular dichroism, nuclear magnetic resonance (NMR) and distance geometry (DG) techniques. The fragment assumes a well-defined secondary structure in TFE and in TFE/water (90/10, v/v) with an alpha-helix encompassing residues 4-9, while in TFE/water (70/30, v/v) a less regular structure was found. The DG results in the micellar system evidence the presence of a distorted alpha-helical conformation involving residues 4-8. Our results reveal that the isolated Antennapedia recognition helix III tend to preserve in solution the alpha-helical conformation even if separated from the rest of the molecule.

Animals↗
PubMed2005

Long term outcome in patients with silent versus symptomatic ischaemia during dobutamine stress echocardiography.

OBJECTIVES: To compare the long term prognosis of patients having silent versus symptomatic ischaemia during dobutamine stress echocardiography (DSE). DESIGN: Observational study. SETTING: Tertiary referral centre. PATIENTS: 931 patients who experienced stress induced myocardial ischaemia during DSE. RESULTS: Silent ischaemia was present in 643 of 931 patients (69%). The number of dysfunctional segments at rest (mean (SD) 9.6 (5.1) v 8.8 (5.0), p = 0.1) and of ischaemic segments (3.5 (2.2) v 3.8 (2.1), p = 0.2) was comparable in both groups. During a mean (SD) follow up of 5.5 (3.3) years, there were 169 (18%) cardiac deaths and 86 (9%) non-fatal infarctions. Multivariable Cox regression analysis showed age (hazard ratio (HR) 1.1, 95% confidence interval (CI) 1.02 to 1.05), previous myocardial infarction (HR 1.4, 95% CI 1.1 to 2.0), and number of ischaemic segments during the test (HR 2.0, 95% CI 1.0 to 3.7) as independent predictors of cardiac death and myocardial infarction. For every additional ischaemic segment there was a twofold increment in risk of late cardiac events. The annual cardiac death or myocardial infarction rate was 3.0% in patients with symptomatic ischaemia and 4.6% in patients with silent ischaemia (p < 0.01). Silent induced ischaemia was an independent predictor of cardiac death and myocardial infarction (HR 1.7, 95% CI 1.1 to 2.0). During follow up symptomatic patients were treated more often with cardioprotective therapy (p < 0.01) and coronary revascularisation (145 of 288 (50%) v 174 of 643 (27%), p < 0.001). CONCLUSIONS: Patients with silent ischaemia had a similar extent of myocardial ischaemia during DSE compared to patients with symptomatic ischaemia but received less cardioprotective treatment and coronary revascularisation and experienced a higher cardiac event rate.

Angina Pectoris↗
PubMed2004

Positive patch tests to Euro coins in nickel-sensitized patients.

BACKGROUND: Many efforts have been made to prevent nickel allergy, the most frequent contact allergy in industrialized countries, by identifying acceptable limits of exposure. Even though coins are not covered by the EU Nickel Directive, some authors suggest that nickel release from coins during handling may elicit contact dermatitis in nickel-allergic people. OBJECTIVES: To evaluate sensitivity to nickel released from coins in nickel-allergic patients and to verify whether nickel release from the new Euro coins may elicit stronger cutaneous reactivity than from old Italian lire coins. METHODS: Twenty-five nickel-allergic patients were patch tested with 1- and 2-Euro coins, 1-, 2- and 50-Euro cent coins, and 100 and 500 Italian lire coins. Ten healthy nonnickel-allergic control individuals were also tested. RESULTS: Nineteen patients had positive patch tests to 1- and 2-Euro coins. One was also positive to 1- and 2-Euro cent coins, four to 50-Euro cent coins, and 13 to the 500-lire coin. None had a positive patch test to the 100-lire coin. The number and degree of positive patch tests to coins were related to nickel content. CONCLUSIONS: Euro coins may be potentially more dangerous than old Italian coins. Coins containing little or no nickel should be chosen for coinage to prevent sensitization and to avoid exacerbation of contact dermatitis in nickel-allergic patients.

Adolescent↗
PubMed2004

In vitro and in vivo characterization of Indium-111 and Technetium-99m labeled CCK-8 derivatives for CCK-B receptor imaging.

Cholecystokinin (CCK) receptors of the subtype B (CCK-BR) have been shown to be overexpressed in certain neuroendocrine tumors including medullary thyroid cancer. Our recent work has focused on new methods to radiolabel the CCK8 peptide with 111In or 99mTc for CCK-B receptor imaging. Derivatives of CCK8 were obtained by addition at the N-terminus in solid phase of a DTPA derivative (DTPAGlu) linked through a glycine spacer (DTPAGlu-G-CCK8) or cysteine, glycine and a diphenylphosphinopropionyl moiety (PhosGC-CCK8) for labeling with 111In and 99mTc, respectively. CCK-BR overexpressing A431 cancer cell lines were utilized to characterize in vitro properties of the two compounds as well as for generating xenografts in nude mice for in vivo characterization. Both 111In-DTPAGlu-G-CCK8 and 99mTcPhosGC-CCK8 showed similar binding affinities for CCK-BR with dissociation constants of 20-40 nM, were internalized after interaction with the receptor and displayed prolonged cellular retention times. Specific in vivo interaction with the receptor of both CCK8 analogs was observed in our animal model. 111In-DTPAGlu-G-CCK8 showed better target to non-target ratios, although it appeared to be rapidly metabolized after injection and activity cleared through the kidneys. 99mTc-PhosGC-CCK8 was more stable in vivo but showed marked hepatobiliary clearance with resulting high background activity in the bowel. The rapid clearance and lower background obtained with 111In-DTPAGlu-G-CCK8 make this a better candidate for further development.

Animals↗
PubMed2004

Peptide nucleic acids (PNA)-DNA chimeras targeting transcription factors as a tool to modify gene expression.

Peptide nucleic acids (PNAs)-DNA chimeras have been recently described as DNA mimics constituted of a part of PNA and of a part of DNA. We have demonstrated that double stranded molecules based on PNA-DNA chimeras bind to transcription factors in a sequence-dependent manner. Accordingly, these molecules can be used for transcription factor decoy (TFD) pharmacotherapy. Effects of double stranded PNA-DNA chimeras targeting NF-kappaB and Sp1 were determined on in vitro cultured human cells and were found to be comparable to those observed using double-stranded DNA decoys. The TFD molecules based on PNA-DNA chimeras can be further engineered by addition of short peptides facilitating cell penetration and nuclear localization. Therefore, these engineered molecules could be of great interest for in vivo experiments for non-viral gene therapy of a variety of diseases, including neoplastic and viral diseases, for which the TFD approach has been already demonstrated as a very useful strategy.

Apoptosis↗
PubMed2003

Construct validity of the abbreviated mental test in older medical inpatients.

OBJECTIVES: To evaluate validity and internal structure of the Abbreviated Mental Test (AMT), and to assess the dependence of the internal structure upon the characteristics of the patients examined. DESIGN: Cross-sectional examination using data from the Italian Group of Pharmacoepidemiology in the Elderly (GIFA) database. SETTING: Twenty-four acute care wards of Geriatrics or General Medicine. PARTICIPANTS: Two thousand eight hundred and eight patients consecutively admitted over a 4-month period. MEASUREMENTS: Demographic characteristics, functional status, medical conditions and performance on AMT were collected at discharge. Sensitivity, specificity and predictive values of the AMT <7 versus a diagnosis of dementia made according to DSM-III-R criteria were computed. The internal structure of AMT was assessed by principal component analysis. The analysis was performed on the whole population and stratified for age (<65, 65-80 and >80 years), gender, education (<6 or >5 years) and presence of congestive heart failure (CHF). RESULTS: AMT achieved high sensitivity (81%), specificity (84%) and negative predictive value (99%), but a low positive predictive value of 25%. The principal component analysis isolated two components: the former component represents the orientation to time and space and explains 45% of AMT variance; the latter is linked to memory and attention and explains 13% of variance. Comparable results were obtained after stratification by age, gender or education. In patients with CHF, only 48.3% of the cumulative variance was explained; the factor accounting for most (34.6%) of the variance explained was mainly related to the three items assessing memory. CONCLUSION: AMT >6 rules out dementia very reliably, whereas AMT <7 requires a second level cognitive assessment to confirm dementia. AMT is bidimensional and maintains the same internal structure across classes defined by selected social and demographic characteristics, but not in CHF patients. It is likely that its internal structure depends on the type of patients. The use of a sum-score could conceal some part of the information provided by the AMT.

Aged↗
PubMed2003

Construct validity of the 15-item geriatric depression scale in older medical inpatients.

The construct validity of the 15-item Geriatric Depression Scale (sfGDS) has been assessed in selected populations. The aim of this study was to assess the appropriateness of applying the sfGDS to unselected older inpatients. The main component analysis of sfGDS was performed in 2032 medical inpatients (mean age = 76.3 +/- 8.4). sfGDS did not qualify as a unidimensional test. Three factors explained 47.7% of variance and explored the following dimensions: positive attitude toward life, distressing thoughts/negative judgment about the own condition, and inactivity/reduced self-esteem. The internal homogeneity was poor (Cronbach's alpha = .46). A higher fraction of variance was explained in patients independent in all or dependent in > or = 1 activity of daily living (ADL). In older medical inpatients, sfGDS is not a single construct, which prevents the univocal interpretation of the final score. The higher fraction of explained variance in patients with comparable ADL performance probably reflects the dependency of affective from physical status.

Activities of Daily Living↗
PubMed2002

Radiolabeling approaches for cholecystokinin B receptor imaging.

Regulatory peptides and their analogs are being extensively investigated as radiopharmaceuticals for cancer imaging. In particular, cholecystokinin (CCK) receptors of the subtype B (CCK-BR) have been shown to be overexpressed in certain neuroendocrine tumors including medullary thyroid cancer. Our recent work has focused on new methods to radiolabel the CCK8 peptide with (111)In or (99m)Tc for the purpose of developing radiopharmaceuticals for in vivo CCK-B receptor imaging. Labeling of CCK8 with (111)In was achieved at the N-terminus of the peptide by adding, in solid phase, a glutamate coupled diethylenetriaminepentaacetic acid (DTPA) moiety through a glycine linker, yielding DTPA-Glu-G-CCK8. For labeling with (99m)Tc, the CCK8 peptide was modified at its N-terminus by introducing, in the following order--cysteine, glycine, and a diphenylphosphinopropionyl moiety--giving a 10-residue peptide derivative, Phos-GC-CCK8. A cell culture model was developed for the purpose of evaluating the binding properties of these two ligands. The human epidermoid carcinoma cell line, A431, was transfected with a plasmid containing the full coding sequence of the human CCK-BR under a strong viral promoter, obtaining a number of receptors in the range of 2-5 x 10(6) per cell. Control cells were transfected with vector alone. An animal tumor model utilizing these two cell lines was developed to evaluate the specificity of interaction with the CCK-BR and biodistribution properties of the compounds. CCK-BR positive and control cells were subcutaneously injected in opposite flanks of CD1 female nude mice in order to obtain xenografts differing only in their ability to express CCK-B receptors. High performance liquid chromatography (HPLC) and other chromatographic methods were utilized to assess stability of the radiolabeled compounds after injection. Both (111)In-DTPA-Glu-G-CCK8 and (99m)Tc-Phos-GC-CCK8 showed similar binding affinities for cultured CCK-BR expressing cells, with dissociation constants in the range of 20-40 nM. With the two xenograft approach, we were able to demonstrate specific interaction with the receptor of both CCK analogs in our animal model. The data obtained shows rapid specific localization of both compounds on the CCK-BR overexpressing xenografts. Both tracers show rapid plasma clearance of unbound peptide. Clearance of (111)In-DTPA-Glu-G-CCK8 appears to be preferentially through the kidneys, whereas (99m)Tc-Phos-GC-CCK8 clearance occurs both through kidneys and the hepatobiliary system. Both our labeling approaches appear adequate for clinical use of peptide based radiopharmaceuticals, although (99m)Tc-Phos-GC-CCK8 shows elevated accumulation in the gastrointestinal tract, which causes high background activity.

Animals↗
PubMed2001

Hypotension and cognitive impairment: Selective association in patients with heart failure.

BACKGROUND: Arterial hypotension has been associated with increased risk of dementia in some large prospective studies; and cognitive impairment is common among elderly with left ventricular function. The authors assessed whether arterial hypotension might be associated with cognitive impairment among older subjects with heart failure. METHODS: This study involved all 13,635 patients (of whom 1,583 had heart failure) without cerebrovascular disease or AD, admitted to 81 Italian academic hospitals in 1995 and 1997. The association between blood pressure and cognitive impairment (as indicated by a Hodkinson Mental Test score < 7) according to the presence of heart failure was assessed by univariate analyses, including linear discriminant analysis. This association was also verified by multivariate analyses after stratifying for diagnosis of heart failure. RESULTS: Cognitive impairment was found in 26% of patients with heart failure and in 19% of remaining subjects (Fisher exact p < 0.0001). Blood pressure levels did not differ according to diagnosis of heart failure, but discriminant analysis indicated that systolic blood pressure levels below 130 mm Hg predicted cognitive impairment only among participants with heart failure. Among such participants, systolic blood pressure was associated with cognitive impairment in multiple logistic regression modeling (for 10 mm Hg intervals, OR = 0.78; 95% CI = 0.71 to 0.86). Again, this association was not found among participants without heart failure. CONCLUSIONS: Systolic hypotension is selectively associated with cognitive impairment in older patients with heart failure. As early treatment of cardiac low-output states can reverse cognitive dysfunction, the routine management of heart failure should include systematic assessment of cognitive performance.

Aged↗
PubMed2001

The crystal structure of a hyper-thermophilic carboxylesterase from the archaeon Archaeoglobus fulgidus.

The crystal structure of AFEST, a novel hyper-thermophilic carboxylesterase from the archaeon Archaeoglobus fulgidus, complexed with a sulphonyl derivative, has been determined and refined to 2.2 A resolution. This enzyme, which has recently been classified as a member of the hormone- sensitive-lipase (H) group of the esterase/lipase superfamily, presents a canonical alpha/beta hydrolase core, shielded on the C-terminal side by a cap region composed of five alpha-helices. It contains the catalytic triad Ser160, His285 and Asp255, whereby the nucleophile is covalently modified and the oxyanion hole formed by Gly88, Gly89 and Ala161. A structural comparison of AFEST with its mesophilic and thermophilic homologues, Brefeldin A esterase from Bacillus subtilis (BFAE) and EST2 from Alicyclobacillus acidocaldarius, reveals an increase in the number of intramolecular ion pairs and secondary structure content, as well as a significant reduction in loop extensions and ratio of hydrophobic to charged surface area. The variety of structural differences suggests possible strategies for thermostabilization of lipases and esterases with potential industrial applications.

Amino Acid Sequence↗
PubMed2001

Hip fracture in nursing homes: an Italian study on prevalence, latency, risk factors, and impact on mobility.

Hip fracture may cause and/or complicate institutionalization. We undertook this study to define its overall prevalence among the residents of four nursing homes in Central Italy as well as its latency and impact on mobility when it occurred within institutions. We also performed a case control analysis with the aim of identifying potential risk factors for hip fracture in nursing home. Among the 211 residents (160 women, mean age 82.2 +/- 9.29 years, and 51 men, mean age 77.1 +/- 8.9 years), 42 were hip fracture cases, with a prevalence of almost 20%, and a female/male ratio of 6/1.23 fractures preceded institutionalization; of these 19 (17 females and 2 males) occurred within the nursing homes (mean age 83.2 +/- 6.3 years). The average interval between institutionalization and fracture was 74.2 months. The impact of hip fracture on mobility was relevant. The percentage of residents ambulating autonomously fell from 95% to 32% among those who had fractured. Fractured subjects were characterized by worse mobility and function than unfractured subjects, while comorbidity, cognitive functions, and use of psychotropic drugs were similar. Prefracture mobility of fractured subjects was better than that of age-and sex-matched residents who had never fractured their hip. Regarding hip fracture in our nursing home population we can conclude that (1) hip fracture is one of the main causes of institutionalization; (2) in most cases hip fracture occurred late in the course of the nursing home stay; (3) the functional impact of the fracture was relevant when it occurred in institutions. We also suggest that preserved mobility may represent an additional risk factor for hip fracture in nursing homes.

Activities of Daily Living↗
PubMed2001

Structural consequences of metal complexation of cyclo[Pro-Phe-Phe-Ala-Xaa]2 decapeptides.

The conformational features of both free and Ca2+-complexed cyclo[Pro-Phe-Phe-Ala-Xaa]2 (with Xaa= Glu(OtBu), Lys(CIZ), Leu, and Ala) in solution have been determined by NMR spectroscopy and extensive distance-geometry calculations. The decapeptides are conformationally homogeneous in solution and show common structural features in their free and complexed forms. The structures of the free form contain only trans peptide bonds and are topologically similar to the structure of gramicidin-S, folded up in two antiparallel extended structures, stabilized by interstrand hydrogen bonds, and closed at both ends by two beta-turns. In contrast, the Ca2+-complexed peptides present two cis peptide bonds and are generally similar to those observed for the metal-complexed forms of antamanide and related analogues, folded into a saddle shape with two beta-turns. The Glu(OtBu)-, Leu-, and Lys(ClZ)-containing peptides examined here maintain the biological activity of the cyclolinopeptide A in their ability to competitively inhibit cholate uptake. The natural antamanide and cyclolinopeptide A are both able to inhibit the uptake of bile salts into hepatocytes. They share the same postulated active sequence Pro-Phe-Phe. Based on our structural results, we conclude that the ability to adopt a global conformation, characterized by a clear amphipathic separation of hydrophobic and hydrophilic surfaces, is an important feature for the functioning of this class of peptides.

Biological Transport↗
PubMed2001

Synthesis and solution characterization of a porphyrin-CCK8 conjugate.

In this paper we report the synthesis and a detailed NMR solution characterization of a new CCK8 analogue and its indium(III) complex, PK-CCK8 and In-PK-CCK8. The new compounds contain a porphyrin moiety covalently bound through an amide bond to the side chain of a Lys residue introduced at the N-terminus of CCK8. A molecular dynamics simulation, based on the NMR structure of the complex between CCK8 and the N-terminal extracellular arm of the CCK(A) receptor, is also reported. Both the NMR study and the molecular dynamics simulation indicate that the porphyrin-peptide conjugate might be able to bind to the CCK(A) receptor model. The results of the molecular dynamics calculations show that the conformational features of the CCK8/CCK(A) receptor model complex and of the PK-CCK8/CCK(A) receptor-model complex are similar. This evidence supports the view that the introduction of the porphyrin-Lys moiety does not influence the mode of ligand binding to the CCK(A) receptor model. The NMR structure of PK-CCK8 in DMSO consists of a well defined pseudo-helical N-terminal region, while the C-terminal region is flexible. Moreover, the absence of NOE contacts between the porphyrin and the peptide indicates that the macrocyclic ring is directed away from the peptide region involved in the binding with the receptor.

Computer Simulation↗
PubMed2001

Specific IgA to lactic acid bacteria in feces of children consuming milk fermented by yoghurt symbiosis and Lactobacillus casei (Danone strain DN 114 001).

An immunoreactive role of lactic acid bacteria established in animals has seldom been investigated in humans. In a large-scale clinical study, children from day-care centers received either yoghurt (Y), milk fermented by yoghurt symbiosis and Lactobacillus casei (DN 114 001) (YC), or gelified milk (GM) as diet supplements during two 30-day supplementation periods separated by one 30-day period without supplementation. Feces samples were collected before, during, and after the 2nd supplementation period. Proteins were extracted in a buffer containing enzymatic inhibitors. IgA levels were assessed and adjusted to the weight of feces samples. Specific IgA to lactic acid bacteria strains (Streptococcus thermophilus 8901A, 8902A; Lactobacillus bulgaricus; Lactobacillus casei) present in Y and YC were assayed in ELISA and adjusted to individual IgA levels. Mean levels of fecal IgA were within reported ranges for pediatric populations of similar age. IgA levels decreased significantly but transiently in children receiving Y, and increased significantly in children receiving GM, but did not vary in the group of children who were given YC. Specific IgA to the 4 strains tested increased significantly during the supplementation period only in the group of children receiving GM, while it was transient and not significant in children receiving YC. No variation was noted in children given Y Specific IgA to lactic acid bacteria can be assayed in feces. Supplementation with fermented milks might induce a mucosal tolerance to environmental flora.

Animals↗
PubMed2001

Treatment of osteoporosis among older adults discharged from hospital in Italy.

OBJECTIVE: Osteoporosis and its complications represent one of the most important causes of morbidity and mortality among the elderly. Despite the availability of several drugs deemed effective at reducing the incidence of fractures, only a minority of patients receive pharmacological treatment. We studied patients with a diagnosis of osteoporosis at discharge from hospital in Italy to identify predictors of receiving specific pharmacological treatment and to analyse how the pattern of drug prescription has changed in the last decade. METHODS: We analysed data from a multicentre pharmacoepidemiology study that collected data on hospitalised patients throughout Italy. Patients with a diagnosis of osteoporosis admitted during five different surveys in 1988, 1991, 1993, 1995 and 1997 were considered for the present study. RESULTS: Of 863 patients with a diagnosis of osteoporosis, 461 (53.4%) received treatment. Age [odds ratio (OR) 0.86 for each decade of increment, 95% confidence interval (CI) 0.73, 0.99], male gender (OR 0.67, 95% CI 0.44, 0.99), number of comorbid conditions (4-5 vs. 0-3 conditions: OR 0.66, 95% CI 0.47, 0.91; 6 or more vs. 0-3 conditions: OR 0.47, 95% CI 0.31, 0.72) and number of medications (OR 0.92 for each drug increase, 95% CI 0.85, 0.99) were all associated with a reduced likelihood of receiving pharmacological treatment for osteoporosis. In contrast, concomitant corticosteroid use (OR 2.00, 95% CI 1.05, 3.80), admission for hip or vertebral fracture (OR 2.10, 95% Cl 1.12, 3.93) and year of survey (OR 1.11, 95% CI 1.01, 1.24) were independent predictors of a higher treatment rate. Among individual drugs, calcitonin use remarkably declined from 42.1% in 1988 to 0.8% in 1997 (P for trend <0.001), while bisphosphonate prescriptions increased from 1.3% in 1988 to 34.9% in 1997 (P for trend <0.001). Prescription of calcium did not change significantly throughout the decade examined, while vitamin D had a twofold increase (14.2% in 1988 to 26.2% in 1997, P for trend <0.001). CONCLUSIONS: Among patients discharged from hospital in Italy, osteoporosis is an uncommon diagnosis. Even when the diagnosis is made, osteoporosis is often undertreated, and treatment is reserved for younger and less medically complex patients.

Aftercare↗